Historically, liver was early recognized as superior nutrition for providing factors necessary for the body's production of red blood cells and hemoglobin. Following early studies with liver and liver extracts, intensive investigation over a number of decades of factors found in liver resulted in the isolation of the principal water soluble hematinic vitamins, folic acid (also referred to as vitamin Bc and vitamin M) and vitamin B.sub.12.
Folic acid was the first of these major hematinic vitamins to be made generally available in pure form. From the beginning the cost of folic acid was relatively low. The vitamin was therefore employed primarily orally and the dosages used were quite high. For example, folic acid was commonly supplied as 5, 10, or 20 mg. tablets and doses as high as 400 mg. were given without ill effects. The only real and serious problem encountered with the use of folic acid was that which followed when it was used for what is now recognized to have been for the wrong purpose, i.e. to treat the so-called pernicious anemia patient. Such a patient, of course, is now known to be one who is really deficient in vitamin B.sub.12 secondary to his inability to secrete intrinsic factor, and only sometimes, but not necessarily, also deficient in folic acid.
Progressively over the years various investigators have shown that large oral doses are not really necessary to treat simple folic acid deficiency. Indeed as little as 25 micrograms per day orally have in some instances been shown to be minimally effective in patients deficient in this vitamin. The hematological response which can be induced in adults having megaloblastic anemia with oral doses of folic acid in the range of 25 to 250 micrograms, implies that the minimal daily requirement for folate in the adult is within this range.
The National Academy of Science, National Research Council's Food and Nutrition Board's 1968 Recommended Daily Dietary Allowances list indicated pregnancy as the category of highest need for folate, and specifies 800 micrograms from dietary sources as the R.D.A. (Recommended Daily Dietary Allowance) for folate during pregnancy. The Board also recognizes, however, that pure forms of folate may be effective in doses less than one-fourth of the R.D.A. from dietary sources, or in the case of pregnancy at a dose level as low as 200 micrograms per day.
Vitamin B.sub.12 became available in pure crystalline form several years after folic acid had become available. Unlike folic acid, however, the cost of vitamin B.sub.12 was initially quite high. Accordingly, the usual recommendations were that the vitamin be given preferentially by the intramuscular route of administration. The minimum parenteral dose was therefore defined early for patients with so-called pernicious anemia. It was shown that very small doses given intramuscularly were dramatically effective in these patients, who, as indicated above, now are recognized as having a vitamin B.sub.12 deficiency secondary to a deficiency in their gastric mucosa making them unable to produce their own intrinsic factor.
Low microgram quantities of vitamin B.sub.12 that are effective parenterally were found to be effective orally in the so-called pernicious anemia patient only when given with stomach concentrates. However, the commercially available preparations which contain intrinsic factor from hog stomach were soon found to be unreliable, and plagued with development of resistance to this potentiation of absorption of small microgram amounts of the vitamin. This potential for treatment failure was responsible for the decision by the Food and Drug Administration to place these preparations on prescription status. The unreliability of these preparations was also responsible for the widespread disrepute into which all oral therapy for so-called pernicious anemia fell.
Over the years, however, there have been many published reports that fully document the effecacy and safety of vitamin B.sub.12 administered in various large amounts without intrinsic factor to patients with so-called pernicious anemia. Indeed it has long been known that when large amounts of vitamin B.sub.12 are given orally without intrinsic factor, no difference in response can be demonstrated between normal subjects and patients with intrinsic factor deficiency (the so-called pernicious anemia patient). Following the oral administration of 100 to 100,000 micrograms of radioactive vitamin B.sub.12, approximately the same percentage of the radioactivity administered is detected in the urine of patients with intrinsic factor deficiency and/or normal subjects. Since equal amounts are excreted under these circumstances, equal amounts are also absorbed and estimated to be one percent of the administered dose. From the data of these studies it is known that the oral administration of 500 micrograms of vitamin B.sub.12 per day provides for the absorption of approximately 5 micrograms of the vitamin. The human daily body requirement for vitamin B.sub.12 has been estimated to be between 1 and 5 micrograms or, in some exceptional cases slightly higher.